WO2023029979A1 - Method for preparing glp-1 receptor agonist intermediate - Google Patents

Method for preparing glp-1 receptor agonist intermediate Download PDF

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WO2023029979A1
WO2023029979A1 PCT/CN2022/112721 CN2022112721W WO2023029979A1 WO 2023029979 A1 WO2023029979 A1 WO 2023029979A1 CN 2022112721 W CN2022112721 W CN 2022112721W WO 2023029979 A1 WO2023029979 A1 WO 2023029979A1
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compound
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phenyl
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胡范
周鑫洁
刘东舟
胡海文
刘克楠
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杭州中美华东制药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system

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  • the invention belongs to the technical field of drug synthesis, in particular to an intermediate (S,Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy) of a GLP-1 receptor agonist Phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-hydroxyacrylic acid and (S)-3-((S)-2-(4- ((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S) - a preparation method of 1-phenylpropyl) amino) propionic acid.
  • Invention patent CN102378574B discloses a method for preparing compound I free base by using 4-hydroxyacetophenone as a raw material through 14 steps of nucleophilic substitution, bromination, asymmetric reduction, condensation, and hydrolysis.
  • the preparation of the free base of compound I from compound A requires catalytic hydrogenation and multiple deprotection processes, making the reaction steps longer.
  • the present invention uses intermediate 3 to replace intermediate compound A, and then compound 3 can be prepared by five steps of hydrolysis, reduction, condensation and other reactions to obtain free base I.
  • the preparation of compound 2 from compound 3 requires a hydrolysis process.
  • the literature (US6211235 B1; J.Am.Chem.Soc.2018,140,32,10263) adopts Strong acid hydrolysis. Since the ether bond in compound 3 may be hydrolyzed under acidic conditions, applying this method to the preparation of compound 2 will result in the inversion of the chiral configuration of the generated compound 2, thereby affecting the quality of the product. Therefore, it is urgent to develop a preparation process route of compound 2 with good yield and controllable quality.
  • compound (S,S,S)-1 compound 1 of the new route has 3 chiral centers, and the preparation of compound 1 is an ammoniation reduction reaction. Two chiral centers will be introduced here, and there will be 8 non- Enantiomers, in the actual process development process, there are mainly three isomer impurities (S, R, S)-1, (R, S, S)-1, (S, S, R)-1.
  • Its isomer content is mainly affected by the chiral purity of the starting material and the reduction reaction, wherein compound 1 reacts with S-phenylpropylamine to generate imine first, and then under the action of a reducing agent, compound 1 is asymmetrically synthesized, due to the reaction Selectivity, the main side reaction impurity is (R, S, S)-1 introduced by asymmetric reduction reaction.
  • the formation of impurity (R,S,S)-1 is mainly affected by the reducing agent, and when a single boron reducing agent (such as sodium borohydride) is used, the product is a racemate.
  • the urgent problem to be solved at present is to increase the conversion rate of the reaction without affecting the chiral purity, so as to obtain compound 1 with high yield and high purity.
  • the present invention provides a novel intermediate (S,Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzene of compound I [b][1,4]dioxin-6-yl)-2-hydroxyacrylic acid (compound 2), an economical and effective preparation method, which has the advantages of low cost, high yield and controllable quality, It is more suitable for industrialized production.
  • the inorganic base used in the step a-1) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide; preferably sodium hydroxide.
  • organic acid and inorganic acid aqueous solution are added in batches.
  • the organic acid used in step a-2) is selected from oxalic acid, citric acid, malic acid, succinic acid, maleic acid, fumaric acid, acetic acid, trifluoroacetic acid or propionic acid; preferably acetic acid.
  • the inorganic acid used in step a-22) is selected from hydrochloric acid or sulfuric acid.
  • the organic acid is added first, and then the aqueous solution of the inorganic acid is added twice.
  • the concentration of the inorganic acid is selected from 2-8 mol/L.
  • the reaction temperature of step a-2) is 50-100°C.
  • post-reaction treatment is performed, and the post-treatment includes cooling the reaction liquid, transferring it to water, stirring and crystallizing, and filtering to obtain the crude compound 2.
  • the crude product in the post-treatment, can be further beaten with an organic solvent, the temperature of the beating can be controlled, and the pure compound 2 can be obtained after filtration.
  • the crystallization temperature in post-treatment is 0-40°C.
  • the organic solvent used in the post-treatment is selected from dichloromethane, chloroform, ethyl acetate, methanol, 1,2-dichloroethane, preferably dichloromethane.
  • the beating temperature in post-treatment is selected from 0-40°C, preferably 10-20°C.
  • the present invention also provides a novel intermediate of compound I (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-
  • the method has the advantages of low cost, high yield and controllable quality, and is more suitable for industrial production.
  • the present invention further provides the preparation of (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b]
  • the organic base in the step b-1) is selected from isopropylamine, triethylamine, N-methylmorpholine, piperazine, and N,N-diisopropylethylamine.
  • the reaction temperature in the step b-1) is 5-45°C, preferably 15-35°C.
  • the molar ratio of compound 2, S-phenylpropylamine and organic base in the step b-1) is 1:1.1:1.1 ⁇ 1:4:6.
  • the reaction solvent in step b-1 is selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane.
  • the reducing agent in step b-2) is a combination of MBH(RCOO) 3 and zinc borohydride.
  • the feeding ratio of compound 2, MBH(RCOO) 3 and zinc borohydride in step b-2) is 1:1.1:0.1 ⁇ 1:6:0.6.
  • M is selected from lithium, sodium, and potassium; R is a C6-C10 saturated alkyl group.
  • the reaction solvent in the step b-22) is selected from toluene, xylene, and chlorobenzene.
  • the reaction temperature in step b-22) is 0-40°C.
  • post-reaction treatment is carried out, and the post-treatment includes adding methanol to quench the reaction, then adding DMF to distill off the low-boiling reaction solvent, and then drop Add an alcoholic solvent, crystallize, filter and dry to obtain Compound 1; wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, and n-propanol.
  • the beneficial effects of this technical solution are: increasing the reducing agent component, and adding lithium chloride to promote the reaction, increasing the reaction conversion rate from 80% to 95%, thereby increasing the yield from 70% to 85%, and isomerization
  • the volume content does not increase, and the product quality is guaranteed while improving the yield.
  • the experimental method that does not indicate specific condition in the embodiment is conventional condition usually, or according to the condition suggested by raw material or commodity manufacturer;
  • Known reagents are prepared by conventional methods.
  • Embodiment 1 the preparation of compound 3
  • Embodiment 2 the preparation of compound 2
  • Embodiment 3 the preparation of compound 1 (purity detection is used)
  • Embodiment 4 Comparative example of compound 2 preparation (compound 2 is prepared by one-step acid hydrolysis method)
  • step-by-step hydrolysis method can significantly reduce the content of isomer impurities, thereby improving product quality.
  • Embodiment 5 the preparation of compound 1
  • Preparation of reducing agent add NaBH 4 (2.4g), dioxane (36g), xylene (28.8g) to the reaction flask, and stir at 15°C under temperature control; dropwise add isooctanoic acid (27.42g), dropwise After adding, keep warm and stir. Add a THF solution (8 mL) of zinc borohydride, continue to insulate and stir for 3-4 h, and set aside.
  • Embodiment 6 the comparative example of compound 1 preparation (do not add zinc borohydride and lithium chloride to prepare compound 1)
  • Preparation of reducing agent add NaBH 4 (2.4g), dioxane (36g), xylene (28.8g) to the reaction flask, and stir at 15°C under temperature control; dropwise add isooctanoic acid (27.42g), dropwise After adding, keep warm and stir, set aside.

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Abstract

Provided is a method for preparing (S,Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-hydroxyacrylic acid and (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S)-1-phenylpropyl)amino)propanoic acid. The preparation method has advantages of low cost, high yield and controllable quality, and is more suitable for industrial production.

Description

GLP-1受体激动剂中间体的制备方法The preparation method of GLP-1 receptor agonist intermediate 技术领域technical field
本发明属于药物合成技术领域，具体涉及一种GLP-1受体激动剂的中间体(S,Z)-3-(2-(4-((3,4-二氯苄基)氧基)苯基)-2,3-二氢苯并[b][1,4]二噁英-6-基)-2-羟基丙烯酸和(S)-3-((S)-2-(4-((3,4-二氯苄基)氧基)苯基)-2,3-二氢苯并[b][1,4]二噁英-6-基)-2-(((S)-1-苯基丙基)氨基)丙酸的制备方法。The invention belongs to the technical field of drug synthesis, in particular to an intermediate (S,Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy) of a GLP-1 receptor agonist Phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-hydroxyacrylic acid and (S)-3-((S)-2-(4- ((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S) - a preparation method of 1-phenylpropyl) amino) propionic acid.
背景技术Background technique
(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸二盐酸盐(化合物I)，是非肽类小分子胰高血糖素样肽-1受体(GLP-1R)激动剂，其分子式为C 50H 49Cl 4N 3O 6，分子量为929.76，其化学结构式如下： (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6 ,7,8,9-Hexahydro-[1,4]-dioxine[2,3-g]isoquinoline-8-carboxamido)-3-(4-(2,3 -Dimethylpyridin-4-yl)phenyl)propionic acid dihydrochloride (compound I), is a non-peptide small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, and its molecular formula is C 50 H 49 Cl 4 N 3 O 6 , the molecular weight is 929.76, and its chemical structure is as follows:
Figure PCTCN2022112721-appb-000001
Figure PCTCN2022112721-appb-000001
发明专利CN102378574B公开了以4-羟基苯乙酮为原料，经亲核取代，溴化，不对称还原，缩合，水解等14步反应制备化合物I游离碱的方法。其中由化合物A制备化合物I的游离碱，需要经过催化加氢，多次脱保护过程，使得反应步骤较长。Invention patent CN102378574B discloses a method for preparing compound I free base by using 4-hydroxyacetophenone as a raw material through 14 steps of nucleophilic substitution, bromination, asymmetric reduction, condensation, and hydrolysis. The preparation of the free base of compound I from compound A requires catalytic hydrogenation and multiple deprotection processes, making the reaction steps longer.
Figure PCTCN2022112721-appb-000002
Figure PCTCN2022112721-appb-000002
发明内容Contents of the invention
为了简化现有技术，本发明使用中间体3替代中间体化合物A，然后化合物3再经水解、还原、缩合等5步反应可制得游离碱I。其中由化合物3制备化合物2需要经过一个水解的过程，对于同时含有酰胺键及酯基结构的水解反应，文献中(US6211235 B1；J.Am.Chem.Soc.2018,140,32,10263)采用强酸水解法。由于化合物3中的醚键在酸性条件可能会水解，将该法应用到化合物2的制备，会导致生成的化合物2手性构型翻转， 进而影响产品质量。故亟需开发一条收率佳、质量可控的化合物2的制备工艺路线。In order to simplify the existing technology, the present invention uses intermediate 3 to replace intermediate compound A, and then compound 3 can be prepared by five steps of hydrolysis, reduction, condensation and other reactions to obtain free base I. The preparation of compound 2 from compound 3 requires a hydrolysis process. For the hydrolysis reaction containing both amide bond and ester group structure, the literature (US6211235 B1; J.Am.Chem.Soc.2018,140,32,10263) adopts Strong acid hydrolysis. Since the ether bond in compound 3 may be hydrolyzed under acidic conditions, applying this method to the preparation of compound 2 will result in the inversion of the chiral configuration of the generated compound 2, thereby affecting the quality of the product. Therefore, it is urgent to develop a preparation process route of compound 2 with good yield and controllable quality.
Figure PCTCN2022112721-appb-000003
Figure PCTCN2022112721-appb-000003
进一步优化工艺，使用中间体3替代中间体化合物A，化合物3再经水解、还原、缩合等5步反应可制得化合物I的游离碱。新路线的化合物(S,S,S)-1(化合物1)具有3个手性中心，制备化合物1为氨化还原反应，此处会引入两个手性中心，理论上会有8种非对映体，实际工艺研发过程中，主要有3个异构体杂质(S,R,S)-1、(R,S,S)-1、(S,S,R)-1。其异构体含量主要受起始原料的手性纯度及还原反应的影响，其中化合物1先与S-苯基丙胺反应生成亚胺，然后在还原剂作用下，不对称合成化合物1，由于反应选择性，主要副反应杂质为不对称还原反应引入的(R,S,S)-1。杂质(R,S,S)-1的形成主要受还原剂的影响，当使用单一硼还原剂(如硼氢化钠)时，产物为消旋体。需要通过增加还原剂的位阻来实现不对称合成，但是当还原剂体积过大时，又会造成反应转化率低，影响收率。故目前急需解决的问题就是在不影响手性纯度的情况下，提高反应转化率，以便获得高收率、高纯度的化合物1。Further optimize the process, use intermediate 3 to replace intermediate compound A, and then compound 3 can be hydrolyzed, reduced, condensed and other 5-step reactions to prepare the free base of compound I. The compound (S,S,S)-1 (compound 1) of the new route has 3 chiral centers, and the preparation of compound 1 is an ammoniation reduction reaction. Two chiral centers will be introduced here, and there will be 8 non- Enantiomers, in the actual process development process, there are mainly three isomer impurities (S, R, S)-1, (R, S, S)-1, (S, S, R)-1. Its isomer content is mainly affected by the chiral purity of the starting material and the reduction reaction, wherein compound 1 reacts with S-phenylpropylamine to generate imine first, and then under the action of a reducing agent, compound 1 is asymmetrically synthesized, due to the reaction Selectivity, the main side reaction impurity is (R, S, S)-1 introduced by asymmetric reduction reaction. The formation of impurity (R,S,S)-1 is mainly affected by the reducing agent, and when a single boron reducing agent (such as sodium borohydride) is used, the product is a racemate. It is necessary to increase the steric hindrance of the reducing agent to achieve asymmetric synthesis, but when the volume of the reducing agent is too large, the reaction conversion rate will be low and the yield will be affected. Therefore, the urgent problem to be solved at present is to increase the conversion rate of the reaction without affecting the chiral purity, so as to obtain compound 1 with high yield and high purity.
本发明提供一种化合物I的新型中间体(S,Z)-3-(2-(4-((3,4-二氯苄基)氧基)苯基)-2,3-二氢苯并[b][1,4]二噁英-6-基)-2-羟基丙烯酸(化合物2)的经济、有效的制备方法，该方法具有成本低、收率高、质量可控的优点，更适合于工业化生产。The present invention provides a novel intermediate (S,Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzene of compound I [b][1,4]dioxin-6-yl)-2-hydroxyacrylic acid (compound 2), an economical and effective preparation method, which has the advantages of low cost, high yield and controllable quality, It is more suitable for industrialized production.
本发明提供的制备(S,Z)-3-(2-(4-((3,4-二氯苄基)氧基)苯基)-2,3-二氢苯并[b][1,4]二噁英-6-基)-2-羟基丙烯酸(化合物2)的方法，包括以下步骤：Preparation (S, Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b][1] provided by the present invention , 4] the method of dioxin-6-base)-2-hydroxyacrylic acid (compound 2), comprises the following steps:
a-1)化合物3在无机碱水溶液的作用下使酯基水解；a-1) Compound 3 hydrolyzes the ester group under the action of an aqueous inorganic alkali solution;
a-2)再依次加入有机酸、无机酸水溶液使酰胺水解，得到化合物2。a-2) adding an organic acid and an aqueous solution of an inorganic acid in sequence to hydrolyze the amide to obtain compound 2.
Figure PCTCN2022112721-appb-000004
Figure PCTCN2022112721-appb-000004
在一实施方案中，所述步骤a-1)中使用的无机碱选自氢氧化锂、氢氧化钠、氢氧化钾；优选为氢氧化钠。In one embodiment, the inorganic base used in the step a-1) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide; preferably sodium hydroxide.
在一实施方案中，在所述步骤a-2)中，有机酸、无机酸水溶液分批加入。In one embodiment, in the step a-2), organic acid and inorganic acid aqueous solution are added in batches.
在一实施方案中，所述步骤a-2)中使用的有机酸选自草酸、柠檬酸、苹果酸、琥珀酸、马来酸、富马酸、乙酸、三氟乙酸或丙酸；优选为乙酸。In one embodiment, the organic acid used in step a-2) is selected from oxalic acid, citric acid, malic acid, succinic acid, maleic acid, fumaric acid, acetic acid, trifluoroacetic acid or propionic acid; preferably acetic acid.
在一实施方案中，所述步骤a-2)中使用的无机酸选自盐酸或硫酸。In one embodiment, the inorganic acid used in step a-2) is selected from hydrochloric acid or sulfuric acid.
在一实施方案中，在所述步骤a-2)中，先加入有机酸，后再分两次加入无机酸水溶液。In one embodiment, in the step a-2), the organic acid is added first, and then the aqueous solution of the inorganic acid is added twice.
在一实施方案中，在所述步骤a-2)中，无机酸的浓度选自2～8mol/L。In one embodiment, in the step a-2), the concentration of the inorganic acid is selected from 2-8 mol/L.
在一实施方案中，所述步骤a-2)的反应温度为50～100℃。In one embodiment, the reaction temperature of step a-2) is 50-100°C.
在一实施方案中，步骤a-1)和步骤a-2)反应完成后，进行反应后处理，所述的后处理包括反应液降温，转移至水中搅拌析晶，以及过滤得化合物2粗品。In one embodiment, after the reaction of step a-1) and step a-2), post-reaction treatment is performed, and the post-treatment includes cooling the reaction liquid, transferring it to water, stirring and crystallizing, and filtering to obtain the crude compound 2.
在一实施方案中，在后处理中可进一步将粗品再用有机溶剂打浆，控制打浆温度，过滤后得化合物2纯品。In one embodiment, in the post-treatment, the crude product can be further beaten with an organic solvent, the temperature of the beating can be controlled, and the pure compound 2 can be obtained after filtration.
在一实施方案中，在后处理中所述析晶的温度为0～40℃。In one embodiment, the crystallization temperature in post-treatment is 0-40°C.
在一实施方案中，在后处理中使用的有机溶剂选自二氯甲烷、三氯甲烷、乙酸乙酯、甲醇、1,2-二氯乙烷，优选二氯甲烷。In one embodiment, the organic solvent used in the post-treatment is selected from dichloromethane, chloroform, ethyl acetate, methanol, 1,2-dichloroethane, preferably dichloromethane.
在一实施方案中，后处理中的打浆温度选自0～40℃，优选10～20℃。In one embodiment, the beating temperature in post-treatment is selected from 0-40°C, preferably 10-20°C.
本技术方案的有益效果为：以分步水解的方法替代传统的一步酸水解法，有效降低了副反应的发生，减少手性翻转的发生率，使手性异构体含量由9％降至0.9％，产品质量显著提升，降低后续反应的纯化压力。The beneficial effects of this technical solution are: replacing the traditional one-step acid hydrolysis method with a step-by-step hydrolysis method, effectively reducing the occurrence of side reactions, reducing the incidence of chiral inversion, and reducing the content of chiral isomers from 9% to 0.9%, the product quality is significantly improved, and the purification pressure of subsequent reactions is reduced.
本发明还提供了一种化合物I新型中间体(S)-3-((S)-2-(4-((3,4-二氯苄基)氧基)苯基)-2,3-二氢苯并[b][1,4]二噁英-6-基)-2-(((S)-1-苯基丙基)氨基)丙酸(化合物1)的制备方法，该方法具有成本低、收率高、质量可控的优点，更适合于工业化生产。The present invention also provides a novel intermediate of compound I (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3- The preparation method of dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S)-1-phenylpropyl)amino)propionic acid (compound 1), the method The method has the advantages of low cost, high yield and controllable quality, and is more suitable for industrial production.
本发明进一步提供制备(S)-3-((S)-2-(4-((3,4-二氯苄基)氧基)苯基)-2,3-二氢苯并[b][1,4]二噁英-6-基)-2-(((S)-1-苯基丙基)氨基)丙酸(化合物1)的方法，包括以下步骤：The present invention further provides the preparation of (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b] The method of [1,4]dioxin-6-yl)-2-(((S)-1-phenylpropyl)amino)propionic acid (compound 1), comprising the following steps:
Figure PCTCN2022112721-appb-000005
Figure PCTCN2022112721-appb-000005
b-1)化合物2在有机碱作用下与S-苯基丙胺反应生成亚胺中间体；b-1) Compound 2 reacts with S-phenylpropylamine under the action of an organic base to generate an imine intermediate;
b-2)亚胺中间体在还原剂及LiCl的作用下发生还原反应，得到化合物1。b-2) The imine intermediate undergoes a reduction reaction under the action of a reducing agent and LiCl to obtain compound 1.
在一实施方案中，所述步骤b-1)中的有机碱选自异丙胺、三乙胺、N-甲基吗啉、哌嗪、N,N-二异丙基乙胺。In one embodiment, the organic base in the step b-1) is selected from isopropylamine, triethylamine, N-methylmorpholine, piperazine, and N,N-diisopropylethylamine.
在一实施方案中，所述步骤b-1)中的反应温度为5～45℃，优选15～35℃。In one embodiment, the reaction temperature in the step b-1) is 5-45°C, preferably 15-35°C.
在一实施方案中，所述步骤b-1)中化合物2与S-苯基丙胺及有机碱的投料摩尔比为1:1.1:1.1～1:4:6。In one embodiment, the molar ratio of compound 2, S-phenylpropylamine and organic base in the step b-1) is 1:1.1:1.1˜1:4:6.
在一实施方案中，所述步骤b-1)中的反应溶剂选自四氢呋喃、2-甲基四氢呋喃、二氧六环。In one embodiment, the reaction solvent in step b-1) is selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane.
在一实施方案中，所述步骤b-2)中的还原剂为MBH(RCOO) 3与硼氢化锌的组合物。 In one embodiment, the reducing agent in step b-2) is a combination of MBH(RCOO) 3 and zinc borohydride.
在一实施方案中，所述步骤b-2)中化合物2、MBH(RCOO) 3与硼氢化锌的投料比例为1:1.1:0.1～1:6:0.6。 In one embodiment, the feeding ratio of compound 2, MBH(RCOO) 3 and zinc borohydride in step b-2) is 1:1.1:0.1˜1:6:0.6.
在一实施方案中，所述MBH(RCOO) 3中，M选自锂、钠、钾；R为C6～C10的饱和烷基。 In one embodiment, in the MBH(RCOO) 3 , M is selected from lithium, sodium, and potassium; R is a C6-C10 saturated alkyl group.
在一实施方案中，所述步骤b-2)中的反应溶剂选自甲苯、二甲苯、氯苯。In one embodiment, the reaction solvent in the step b-2) is selected from toluene, xylene, and chlorobenzene.
在一实施方案中，所述步骤b-2)中的反应温度为0～40℃。In one embodiment, the reaction temperature in step b-2) is 0-40°C.
在一实施方案中，步骤b-1)和步骤b-2)反应完成后，进行反应后处理，所述的后处理包括加入甲醇淬灭反应，然后加入DMF蒸馏除去低沸点反应溶剂，然后滴加醇类溶剂，析晶，过滤干燥得化合物1；其中所述的醇类溶剂选自甲醇、乙醇、异丙醇、正丙醇。In one embodiment, after the reaction of step b-1) and step b-2) is completed, post-reaction treatment is carried out, and the post-treatment includes adding methanol to quench the reaction, then adding DMF to distill off the low-boiling reaction solvent, and then drop Add an alcoholic solvent, crystallize, filter and dry to obtain Compound 1; wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, and n-propanol.
本技术方案的有益效果为：增加还原剂组分，并加入氯化锂促进反应进行，将反应转化率由80％提高至95％，从而使收率由70％提升至85％，且异构体含量没有上升，在提升收率的同时，保证产品质量。The beneficial effects of this technical solution are: increasing the reducing agent component, and adding lithium chloride to promote the reaction, increasing the reaction conversion rate from 80% to 95%, thereby increasing the yield from 70% to 85%, and isomerization The volume content does not increase, and the product quality is guaranteed while improving the yield.
附图简要说明Brief description of the drawings
图1-经实施例1～3所述的制备方法制得的化合物1异构体的HPLC谱图Fig. 1-HPLC spectrogram of the compound 1 isomer prepared by the preparation method described in Examples 1-3
实施例Example
下面结合具体实施例对本发明作进一步的详细说明。The present invention will be further described in detail below in conjunction with specific embodiments.
实施例中未注明具体条件的实验方法，通常为常规条件，或按照原料或商品制造厂商所建议的条件；未注明来源的试剂，通常为通过商业途径可购得的常规试剂或者可以由已知的试剂通过常规方法制备得到。The experimental method that does not indicate specific condition in the embodiment, is conventional condition usually, or according to the condition suggested by raw material or commodity manufacturer; Known reagents are prepared by conventional methods.
实施例1：化合物3的制备Embodiment 1: the preparation of compound 3
Figure PCTCN2022112721-appb-000006
Figure PCTCN2022112721-appb-000006
向反应瓶中加入化合物4(83.1g，0.2mol)、化合物5(75.9g，0.3mol)、甲苯(300g)及DMAP(48.9g，0.4mol)，20℃下搅拌反应16小时。TLC监测无化合物4的点。反应结束后，加入5％氯化铵水溶液(820g)。分除水层，有机层用饱和盐水洗涤，有机相浓缩，浓缩液中再加入甲醇/水(500g/500g)搅拌析晶，过滤，干燥得95.2g化合物3，收率88％。 1H NMR(500MHz,d 6-DMSO)δ9.54(s,1H),7.72(d,J＝1.5Hz,1H),7.66(d,J＝8.5Hz,1H),7.46-7.41(m,3H),7.29(d,J＝2Hz,1H),7.18(d,J＝1.5Hz,1H),7.14(s,1H),7.07(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,1H),5.24-5.33(m,1H),5.15(s,2H),4.42-4.40(m,1H),4.01(s,5H),4.17–4.10(m,3H),2.00(s,3H),1.23(t,J＝7.0Hz,3H). Compound 4 (83.1 g, 0.2 mol), compound 5 (75.9 g, 0.3 mol), toluene (300 g) and DMAP (48.9 g, 0.4 mol) were added to the reaction flask, and the reaction was stirred at 20° C. for 16 hours. Spots free of Compound 4 were monitored by TLC. After completion of the reaction, 5% ammonium chloride aqueous solution (820 g) was added. The water layer was separated, the organic layer was washed with saturated brine, and the organic phase was concentrated. Methanol/water (500g/500g) was added to the concentrated solution to stir and crystallize, filtered and dried to obtain 95.2g of compound 3 with a yield of 88%. 1 H NMR (500MHz, d 6 -DMSO) δ9.54(s, 1H), 7.72(d, J=1.5Hz, 1H), 7.66(d, J=8.5Hz, 1H), 7.46-7.41(m, 3H),7.29(d,J=2Hz,1H),7.18(d,J=1.5Hz,1H),7.14(s,1H),7.07(d,J=8.5Hz,2H),6.99(d,J ＝8.5Hz,1H),5.24-5.33(m,1H),5.15(s,2H),4.42-4.40(m,1H),4.01(s,5H),4.17–4.10(m,3H),2.00( s,3H),1.23(t,J=7.0Hz,3H).
实施例2：化合物2的制备Embodiment 2: the preparation of compound 2
Figure PCTCN2022112721-appb-000007
Figure PCTCN2022112721-appb-000007
向反应瓶中加入化合物3(150g，0.28mol)、二氧六环(750g)，保温60℃下搅拌至体系完全溶解，然后滴加45％的氢氧化钠溶液(NaOH 22.12g，H 2O 27mL)。滴完后，保温下搅拌1.5小时。原料反应完后，保温60℃下滴加乙酸(420g)。加完后，升 温至80℃，加入浓盐酸(HCl 277.08g，H 2O 249mL)。加完后，80℃搅拌反应3小时。然后再加入浓盐酸(HCl 277.08g，H 2O 249mL)，加完后继续反应8小时。反应完全后，降至室温，然后将反应液转移至含有1500g水的反应瓶。转移完后，保温15℃下搅拌2小时，然后过滤。滤饼用二氯甲烷15℃下打浆2小时，过滤，真空干燥得113.6g化合物2，收率86％，纯度98.46％。 1H NMR(500MHz,d 6-DMSO)δ13.11(s,1H),9.06(s,1H),7.72(d,J＝1.5Hz,1H),7.65(d,J＝8.5Hz,4H),7.47-7.41(m,4H),7.25(dd,J＝3.5,2.0Hz,2H),7.06(d,J＝9.0Hz,2H),6.92(d,J＝8.5Hz,1H),6.37(s,1H),5.18(d,J＝2.0Hz,1H),5.14(s,2H),4.39–4.37(m,1H),4.11–4.07(m,1H). Add compound 3 (150g, 0.28mol) and dioxane (750g) into the reaction flask, keep stirring at 60°C until the system is completely dissolved, then add dropwise 45% sodium hydroxide solution (NaOH 22.12g, H 2 O 27mL). After dropping, stir under heat preservation for 1.5 hours. After the raw materials were reacted, acetic acid (420 g) was added dropwise at 60° C. while maintaining the temperature. After the addition, the temperature was raised to 80°C, and concentrated hydrochloric acid (HCl 277.08g, H 2 O 249mL) was added. After the addition was complete, the reaction was stirred at 80°C for 3 hours. Then concentrated hydrochloric acid (HCl 277.08 g, H 2 O 249 mL) was added, and the reaction was continued for 8 hours after the addition was completed. After the reaction was complete, the temperature was lowered to room temperature, and then the reaction solution was transferred to a reaction flask containing 1500 g of water. After the transfer, it was stirred at 15° C. for 2 hours, and then filtered. The filter cake was beaten with dichloromethane at 15°C for 2 hours, filtered, and vacuum-dried to obtain 113.6 g of compound 2 with a yield of 86% and a purity of 98.46%. 1 H NMR (500MHz,d 6 -DMSO)δ13.11(s,1H),9.06(s,1H),7.72(d,J=1.5Hz,1H),7.65(d,J=8.5Hz,4H) ,7.47-7.41(m,4H),7.25(dd,J=3.5,2.0Hz,2H),7.06(d,J=9.0Hz,2H),6.92(d,J=8.5Hz,1H),6.37( s,1H),5.18(d,J=2.0Hz,1H),5.14(s,2H),4.39–4.37(m,1H),4.11–4.07(m,1H).
实施例3：化合物1的制备(纯度检测用)Embodiment 3: the preparation of compound 1 (purity detection is used)
向反应瓶中加入化合物2(23.6g，0.05mol)、甲苯(142g)，温度保持在25℃以下，依次加入异丙胺(5.9g，0.1mol)和(S)-苯基丙胺(10.8g，0.08mol)，搅拌。将硼氢化钠(3.7g，0.1mol)和2-乙基戊酸(19.5g，0.15mol)在溶液中混合形成还原剂，15～20℃下加入反应体系中。反应完成后，在减压条件下浓缩。剩余物在热的DMSO中溶解。溶液冷却后，在甲醇中沉淀，过滤，冲洗并干燥得到化合物1(20.2g，收率70％)，由化合物2引入的异构体(R,S,S)-1的含量为0.9％。Add compound 2 (23.6g, 0.05mol) and toluene (142g) to the reaction flask, keep the temperature below 25°C, add isopropylamine (5.9g, 0.1mol) and (S)-phenylpropylamine (10.8g, 0.08mol), stirring. Sodium borohydride (3.7 g, 0.1 mol) and 2-ethylpentanoic acid (19.5 g, 0.15 mol) were mixed in a solution to form a reducing agent, which was added to the reaction system at 15-20°C. After the reaction was complete, it was concentrated under reduced pressure. The residue was dissolved in hot DMSO. After the solution was cooled, it was precipitated in methanol, filtered, washed and dried to obtain compound 1 (20.2 g, yield 70%), and the content of isomer (R, S, S)-1 introduced by compound 2 was 0.9%.
实施例4：化合物2制备的对比实施例(采用一步酸水解法制备化合物2)Embodiment 4: Comparative example of compound 2 preparation (compound 2 is prepared by one-step acid hydrolysis method)
向反应瓶中加入化合物3(54.2g，0.1mol)、二氧六环(542g)并搅拌溶解，加入6mol/L盐酸(220.0g，1.2mol)，升温至85℃反应18小时。TLC监测无化合物3的点。反应结束后，降温并加水(542g)搅拌析晶，过滤得湿品。湿品再用二氯甲烷(300g)打浆，过滤，干燥得到化合物2(40.1g)，收率85％，纯度89.9％。Add compound 3 (54.2g, 0.1mol) and dioxane (542g) into the reaction flask and stir to dissolve, add 6mol/L hydrochloric acid (220.0g, 1.2mol), heat up to 85°C for 18 hours. Spots free of compound 3 were monitored by TLC. After the reaction, cool down and add water (542g) to stir and crystallize, and filter to obtain a wet product. The wet product was further slurried with dichloromethane (300g), filtered and dried to obtain compound 2 (40.1g) with a yield of 85% and a purity of 89.9%.
由于化合物2的异构体检测方法不稳定，以化合物1的特定异构体(R,S,S)-1的含量来评估化合物2的手性纯度。Since the isomer detection method of compound 2 is unstable, the chiral purity of compound 2 was evaluated by the content of the specific isomer (R,S,S)-1 of compound 1.
手性评估：参照实施例3的制备方法制得化合物1，经液相检测，由化合物2引入的异构体(R,S,S)-1的含量为8％。Chiral evaluation: Compound 1 was prepared by referring to the preparation method of Example 3, and the content of isomer (R, S, S)-1 introduced by compound 2 was 8% by liquid phase detection.
对比实验可知，采用分步水解法，可显著降低异构体杂质的含量，从而提高产品质量。It can be seen from comparative experiments that the step-by-step hydrolysis method can significantly reduce the content of isomer impurities, thereby improving product quality.
实施例5：化合物1的制备Embodiment 5: the preparation of compound 1
还原剂的制备：向反应瓶中加入NaBH 4(2.4g)、二氧六环(36g)、二甲苯(28.8g)，控温在15℃下搅拌；滴加异辛酸(27.42g)，滴加完后保温搅拌。加入硼氢化锌的THF溶液(8mL)，继续保温搅拌3-4h，备用。 Preparation of reducing agent: add NaBH 4 (2.4g), dioxane (36g), xylene (28.8g) to the reaction flask, and stir at 15°C under temperature control; dropwise add isooctanoic acid (27.42g), dropwise After adding, keep warm and stir. Add a THF solution (8 mL) of zinc borohydride, continue to insulate and stir for 3-4 h, and set aside.
向反应瓶中加入化合物2(10g)、二氧六环(44.5g)，20℃搅拌溶清，滴加三乙胺(6.6g)并搅拌混匀，然后滴加S-苯基丙胺(8g)。滴毕，继续控温20℃搅拌反应至原料反应完全，然后加入二甲苯(90g)，搅拌溶清。加入LiCl(0.2g)，降温至0℃。滴加配制好的还原剂，加完后20℃下反应。反应结束后滴加甲醇淬灭，加入DMF蒸除低沸点反应溶剂，然后滴加甲醇，搅拌析晶，过滤，真空干燥，得10.64g化合物1，收率：85％，纯度99％，手性纯度：95％。 1H NMR(500MHz,d 6-DMSO)δ7.53(s,1H),7.49-7.41(m,4H),7.32(d,J＝8.5Hz,2H),7.27-7.24(m,1H),7.21(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,2H), 6.82(d,J＝8.0Hz,1H),6.50(s,1H),6.43(d,J＝8.0Hz,1H),5.03(s,2H),4.99(d,J＝8.0Hz,1H),4.29(d,J＝2.0Hz,1H),4.27-4.16(m,1H),3.96-3.92(m,1H),3.83-3.83(m,1H),3.00-2.96(m,2H),2.24-2.17(m,1H),2.06-1.99(m,1H),0.81(t,J＝7.0Hz,3H). Add compound 2 (10g) and dioxane (44.5g) to the reaction flask, stir and dissolve at 20°C, add triethylamine (6.6g) dropwise and mix well, then add S-phenylpropylamine (8g) dropwise ). After dropping, continue to control the temperature at 20° C. and stir the reaction until the raw materials are completely reacted, then add xylene (90 g) and stir to dissolve. LiCl (0.2 g) was added and the temperature was lowered to 0°C. Add the prepared reducing agent dropwise, and react at 20°C after the addition is complete. After the reaction was completed, methanol was added dropwise to quench, and DMF was added to evaporate the low-boiling reaction solvent, then methanol was added dropwise, stirred and crystallized, filtered, and dried in vacuo to obtain 10.64g of compound 1, yield: 85%, purity 99%, chiral Purity: 95%. 1 H NMR (500MHz,d 6 -DMSO)δ7.53(s,1H),7.49-7.41(m,4H),7.32(d,J=8.5Hz,2H),7.27-7.24(m,1H), 7.21(d, J=8.5Hz, 2H), 6.99(d, J=8.5Hz, 2H), 6.82(d, J=8.0Hz, 1H), 6.50(s, 1H), 6.43(d, J=8.0 Hz, 1H), 5.03(s, 2H), 4.99(d, J=8.0Hz, 1H), 4.29(d, J=2.0Hz, 1H), 4.27-4.16(m, 1H), 3.96-3.92(m ,1H),3.83-3.83(m,1H),3.00-2.96(m,2H),2.24-2.17(m,1H),2.06-1.99(m,1H),0.81(t,J＝7.0Hz,3H ).
实施例6：化合物1制备的对比实施例(不加硼氢化锌及氯化锂制备化合物1)Embodiment 6: the comparative example of compound 1 preparation (do not add zinc borohydride and lithium chloride to prepare compound 1)
还原剂的制备：向反应瓶中加入NaBH 4(2.4g)、二氧六环(36g)、二甲苯(28.8g)，控温在15℃下搅拌；滴加异辛酸(27.42g)，滴加完后保温搅拌，备用。 Preparation of reducing agent: add NaBH 4 (2.4g), dioxane (36g), xylene (28.8g) to the reaction flask, and stir at 15°C under temperature control; dropwise add isooctanoic acid (27.42g), dropwise After adding, keep warm and stir, set aside.
向反应瓶中加入化合物2(10g)、二氧六环(44.5g)，20℃搅拌溶清，滴加三乙胺(6.6g)并搅拌混匀，然后滴加S-苯基丙胺(8g)。滴毕，继续控温20℃搅拌反应至原料反应完全，然后加入二甲苯(90g)，搅拌溶清。降温至0℃，滴加配制好的还原剂，加完后20℃下反应。反应结束后滴加甲醇淬灭，加入DMF蒸除低沸点反应溶剂，然后滴加甲醇，搅拌析晶，过滤，真空干燥，得8.76g化合物1，收率：70％，纯度98.5％，手性纯度：95％。Add compound 2 (10g) and dioxane (44.5g) to the reaction flask, stir and dissolve at 20°C, add triethylamine (6.6g) dropwise and stir well, then add S-phenylpropylamine (8g) dropwise ). After dropping, continue to control the temperature at 20° C. and stir the reaction until the raw materials are completely reacted, then add xylene (90 g) and stir to dissolve. Cool down to 0°C, add the prepared reducing agent dropwise, and react at 20°C after the addition. After the reaction was completed, methanol was added dropwise to quench, and DMF was added to evaporate the low-boiling reaction solvent, then methanol was added dropwise, stirred and crystallized, filtered, and dried in vacuo to obtain 8.76g of compound 1, yield: 70%, purity 98.5%, chiral Purity: 95%.
上述实施例仅用于理解本发明的方法和核心思想，而不是限制本发明的范围。对于本领域技术人员来说，在不脱离本发明构思的前提下，进行任何可能的变化或替换，均属于本发明的保护范围。The above-mentioned embodiments are only used for understanding the method and core idea of the present invention, rather than limiting the scope of the present invention. For those skilled in the art, any possible changes or substitutions without departing from the concept of the present invention fall within the protection scope of the present invention.

Claims (8)

  1. 用于制备(S)-3-((S)-2-(4-((3,4-二氯苄基)氧基)苯基)-2,3-二氢苯并[b][1,4]二噁英-6-基)-2-(((S)-1-苯基丙基)氨基)丙酸的方法，其包括如下步骤：For the preparation of (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2,3-dihydrobenzo[b][1 , 4] the method of dioxin-6-base)-2-(((S)-1-phenylpropyl) amino) propionic acid, it comprises the steps:
    Figure PCTCN2022112721-appb-100001
    Figure PCTCN2022112721-appb-100001
    a-1)化合物3在无机碱水溶液的作用下使酯基水解；a-1) Compound 3 hydrolyzes the ester group under the action of an aqueous inorganic alkali solution;
    a-2)依次加入有机酸、无机酸水溶液使酰胺水解，得到(S,Z)-3-(2-(4-((3,4-二氯苄基)氧基)苯基)-2,3-二氢苯并[b][1,4]二噁英-6-基)-2-羟基丙烯酸(化合物2)；a-2) sequentially add organic acid and inorganic acid aqueous solution to hydrolyze the amide to obtain (S, Z)-3-(2-(4-((3,4-dichlorobenzyl)oxy)phenyl)-2 ,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-hydroxyacrylic acid (compound 2);
    Figure PCTCN2022112721-appb-100002
    Figure PCTCN2022112721-appb-100002
    b-1)化合物2在有机碱作用下与S-苯基丙胺反应生成亚胺中间体；b-1) Compound 2 reacts with S-phenylpropylamine under the action of an organic base to generate an imine intermediate;
    b-2)亚胺中间体在还原剂及LiCl的作用下发生还原反应，得到(S)-3-((S)-2-(4-((3,4-二氯苄基)氧基)苯基)-2,3-二氢苯并[b][1,4]二噁英-6-基)-2-(((S)-1-苯基丙基)氨基)丙酸(化合物1)。b-2) The imine intermediate undergoes a reduction reaction under the action of a reducing agent and LiCl to obtain (S)-3-((S)-2-(4-((3,4-dichlorobenzyl)oxy )phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S)-1-phenylpropyl)amino)propanoic acid ( Compound 1).
  2. 如权利要求1所述方法，其中所述步骤a-1)中使用的无机碱选自氢氧化锂、氢氧化钠、氢氧化钾，优选为氢氧化钠。The method according to claim 1, wherein the inorganic base used in the step a-1) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide.
  3. 如权利要求1或2所述的方法，其中：The method of claim 1 or 2, wherein:
    所述步骤a-2)中的有机酸选自草酸、柠檬酸、苹果酸、琥珀酸、马来酸、富马酸、乙酸、三氟乙酸或丙酸，优选为乙酸；The organic acid in the step a-2) is selected from oxalic acid, citric acid, malic acid, succinic acid, maleic acid, fumaric acid, acetic acid, trifluoroacetic acid or propionic acid, preferably acetic acid;
    和/或，所述步骤a-2)中的无机酸选自盐酸或硫酸；And/or, the inorganic acid in the step a-2) is selected from hydrochloric acid or sulfuric acid;
    和/或，在所述步骤a-2)中先加入有机酸，后再分两次加入无机酸水溶液；And/or, in the step a-2), the organic acid is added first, and then the aqueous inorganic acid solution is added in two times;
    和/或，所述步骤a-2)的反应温度为50～100℃；And/or, the reaction temperature of step a-2) is 50-100°C;
    和/或，所述步骤a-2)中无机酸的浓度选自2～8mol/L。And/or, the concentration of the inorganic acid in the step a-2) is selected from 2-8 mol/L.
  4. 如权利要求1至3中任一项所述的方法，其中：The method of any one of claims 1 to 3, wherein:
    步骤a-1)和步骤a-2)完成后，进行反应后处理，所述的后处理包括反应液降温，转移至水中搅拌析晶，以及过滤得化合物2粗品；After step a-1) and step a-2) are completed, post-reaction treatment is carried out. The post-treatment includes cooling the reaction solution, transferring it to water, stirring and crystallizing, and filtering to obtain the crude compound 2;
    和/或，在所述后处理中析晶的温度为0～40℃；And/or, the crystallization temperature in the post-treatment is 0-40°C;
    和/或，所述后处理中使用的有机溶剂选自二氯甲烷、三氯甲烷、乙酸乙酯、甲醇、1,2-二氯乙烷，优选为二氯甲烷；And/or, the organic solvent used in the post-treatment is selected from dichloromethane, chloroform, ethyl acetate, methanol, 1,2-dichloroethane, preferably dichloromethane;
    和/或，所述后处理中的打浆温度选自0～40℃，优选10～20℃。And/or, the beating temperature in the post-treatment is selected from 0-40°C, preferably 10-20°C.
  5. 如权利要求1至4中任一项所述的方法，其中：The method according to any one of claims 1 to 4, wherein:
    所述步骤b-1)中的有机碱选自异丙胺、三乙胺、N-甲基吗啉、哌嗪、N,N-二异丙基乙胺；The organic base in the step b-1) is selected from isopropylamine, triethylamine, N-methylmorpholine, piperazine, N,N-diisopropylethylamine;
    和/或，所述步骤b-1)中的反应温度为5～45℃，优选15～35℃；And/or, the reaction temperature in the step b-1) is 5-45°C, preferably 15-35°C;
    和/或，所述步骤b-1)中化合物2、S-苯基丙胺及有机碱的投料摩尔比为1:1.1:1.1～1:4:6；And/or, the molar ratio of compound 2, S-phenylpropylamine and organic base in the step b-1) is 1:1.1:1.1～1:4:6;
    和/或，所述步骤b-1)中的反应溶剂选自四氢呋喃、2-甲基四氢呋喃、二氧六环。And/or, the reaction solvent in the step b-1) is selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane.
  6. 如权利要求1至5中任一项所述的方法，其中：The method according to any one of claims 1 to 5, wherein:
    所述步骤b-2)中的还原剂为MBH(RCOO) 3与硼氢化锌的组合物； The reducing agent in the step b-2) is the composition of MBH (RCOO) 3 and zinc borohydride;
    和/或，所述步骤b-2)中化合物2、MBH(RCOO) 3与硼氢化锌的投料比例为1:1.1:0.1～1:6:0.6； And/or, the feeding ratio of compound 2, MBH(RCOO) 3 and zinc borohydride in the step b-2) is 1:1.1:0.1～1:6:0.6;
    和/或，所述MBH(RCOO) 3中，M选自锂、钠、钾；R为C 6～10的饱和烷基； And/or, in the MBH(RCOO) 3 , M is selected from lithium, sodium, and potassium; R is a saturated alkyl group with C 6-10 ;
    和/或，所述步骤b-2)中的反应溶剂选自甲苯、二甲苯、氯苯；And/or, the reaction solvent in the step b-2) is selected from toluene, xylene, chlorobenzene;
    和/或，所述步骤b-2)中的反应温度为0～40℃。And/or, the reaction temperature in the step b-2) is 0-40°C.
  7. 如权利要求1至6中任一项所述的方法，其中，步骤b-1)和步骤b-2)完成后，进行反应后处理，所述的后处理包括加入甲醇淬灭反应，然后加入DMF蒸馏除去低沸点反应溶剂，然后滴加醇类溶剂，析晶，过滤干燥得化合物1；其中所述的醇类溶剂选自甲醇、乙醇、异丙醇、正丙醇。The method according to any one of claims 1 to 6, wherein, after step b-1) and step b-2) are completed, post-reaction treatment is carried out, and the post-treatment includes adding methanol to quench the reaction, and then adding DMF was distilled to remove the low-boiling reaction solvent, and then an alcoholic solvent was added dropwise, crystallized, and filtered to dry to obtain Compound 1; wherein the alcoholic solvent was selected from methanol, ethanol, isopropanol, and n-propanol.
  8. 如权利要求1至7中任一项所述的方法在制备式I化合物(S)-2-(3S,8S)-3-(4-(3,4-二氯苄氧基)苯基-7-((S)-1-苯丙基)-2,3,6,7,8,9-六氢-[1,4]-二氧杂环己烯并[2,3-g]异喹啉-8-甲酰氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸二盐酸盐中的用途。The method as described in any one of claims 1 to 7 is in the preparation of formula I compound (S)-2-(3S, 8S)-3-(4-(3,4-dichlorobenzyloxy) phenyl- 7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]iso Use in quinoline-8-carboxamido)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid dihydrochloride.
PCT/CN2022/112721 2021-09-03 2022-08-16 Method for preparing glp-1 receptor agonist intermediate WO2023029979A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1764647A (en) * 2003-03-26 2006-04-26 埃科特莱茵药品有限公司 Tetrahydroisoquinolyl acetamide derivatives for use as orexin receptor antagonists
CN102378574A (en) * 2009-03-30 2012-03-14 转化技术制药公司 Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof
WO2021242806A1 (en) * 2020-05-28 2021-12-02 Vtv Therapeutics Llc Intermediates and methods for preparing a glp-1 receptor agonist
WO2021238962A1 (en) * 2020-05-28 2021-12-02 杭州中美华东制药有限公司 Method for preparing glp-1 receptor agonist

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1764647A (en) * 2003-03-26 2006-04-26 埃科特莱茵药品有限公司 Tetrahydroisoquinolyl acetamide derivatives for use as orexin receptor antagonists
CN102378574A (en) * 2009-03-30 2012-03-14 转化技术制药公司 Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof
WO2021242806A1 (en) * 2020-05-28 2021-12-02 Vtv Therapeutics Llc Intermediates and methods for preparing a glp-1 receptor agonist
WO2021238962A1 (en) * 2020-05-28 2021-12-02 杭州中美华东制药有限公司 Method for preparing glp-1 receptor agonist

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